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. 2015 Dec 14;10(12):e0144958.
doi: 10.1371/journal.pone.0144958. eCollection 2015.

Distributions of Globotriaosylceramide Isoforms, and Globotriaosylsphingosine and Its Analogues in an α-Galactosidase A Knockout Mouse, a Model of Fabry Disease

Hideaki Sueoka  1 , Mikio Aoki  1 , Takahiro Tsukimura  2 , Tadayasu Togawa  2 , Hitoshi Sakuraba  3
Affiliations

Distributions of Globotriaosylceramide Isoforms, and Globotriaosylsphingosine and Its Analogues in an α-Galactosidase A Knockout Mouse, a Model of Fabry Disease

Hideaki Sueoka et al. PLoS One. .

Abstract

Fabry disease is caused by deficient activity of α-galactosidase A (GLA) and characterized by systemic accumulation of glycosphingolipids, substrates of the enzyme. To gain insight into the pathogenesis of Fabry disease based on accumulated substrates, we examined the tissue and plasma distributions of globotriaosylceramide (Gb3) isoforms, and globotriaosylsphingosine (lyso-Gb3) and its analogues in a GLA knockout mouse, a model of Fabry disease, by means of liquid chromatography-mass spectrometry and nano-liquid chromatography-tandem mass spectrometry, respectively. The results revealed that the contents of these substrates in the liver, kidneys, heart, and plasma of GLA knockout mice were apparently higher than in those of wild-type ones, and organ specificity in the accumulation of Gb3 isoforms was found. Especially in the kidneys, accumulation of a large amount of Gb3 isoforms including hydroxylated residues was found. In the GLA knockout mice, the proportion of hydrophobic Gb3 isoforms was apparently higher than that in the wild-type mice. On the other hand, hydrophilic residues were abundant in plasma. Unlike that of Gb3, the concentration of lyso-Gb3 was high in the liver, and the lyso-Gb3/Gb3 ratio in plasma was significantly higher than those in the organs. The concentration of lyso-Gb3 was apparently higher than those of its analogues in the organs and plasma from both the GLA knockout and wild-type mice. This information will be useful for elucidating the basis of Fabry disease.

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Conflict of interest statement

Competing Interests: This study received funding from Sumitomo Dainippon Pharma Co., Ltd. Co-authors H. Sueoka and M. Aoki are employees of Sumitomo Dainippon Pharma Co., Ltd. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1
Fig 1. Lyso-Gb3 analogues and Gb3 Isoforms.
(A) Chemical structure of Lyso-Gb3 and sphingosine modification of lyso-Gb3 analogues. (B) Chemical structure of Gb3(d18:1-C16:0) and ceramide modification of Gb3 isoforms having various fatty acids linked with various sphingosine moieties corresponding to lyso-Gb3 and four analogues.
Fig 2
Fig 2. The distributions of Gb3 isoforms in organs and plasma of the wild-type and GLA knockout mice.
Numbers along the x-axis are elution orders from the RP column and correspond to numbers in Table 1.
Fig 3
Fig 3. The relative abundance of lyso-Gb3 analogues as to lyso-Gb3 in organs and plasma of the wild-type and GLA knockout mice.
See this image and copyright information in PMC

References

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